The successful treatment of refractory autoimmune hemolytic anemia with rituximab in a patient with chronic lymphocytic leukemia

The most frequent autoimmune complication in chronic lymphocytic leukemia (CLL) is autoimmune hemolytic anemia (AIHA). There are various treatment modalities; however, there is not much experience with the use of the chimeric anti-CD20 monoclonal antibody rituximab in the autoimmune complications of CLL. Here, we present our patient with CLL and AIHA whose AIHA was unresponsive to various treatment modalities. The administration of 375 mg/m(2)/day rituximab weekly for four cycles halted hemolysis and resulted in resolution of the patient's anemia. One year after therapy, the patient is well with a normal blood count. Rituximab might be preferred over other treatment modalities in the autoimmune complications of CLL because it is effective and has fewer side effects than other therapies.     

The biological and clinical relationship between CD5+23+ monoclonal B-cell lymphocytosis and chronic lymphocytic leukaemia

A CD5(+)23(+) monoclonal B-cell population is detectable in approximately 3% of the general adult population. The phenotype of the monoclonal CD5(+)23(+) B cells is identical to chronic lymphocytic leukaemia (CLL) with respect to a large number of proteins in addition to the standard diagnostic markers used to identify CLL. Studies in CLL families and direct assessment of genetic features indicate a close biological association between indolent CLL and the CLL-phenotype cells detected in individuals with a normal blood count. Patients with a CLL-phenotype monoclonal B-cell lymphocytosis (MBL) often have increasing CLL cell counts with time and some progress to a stage requiring treatment. Analysis of intraclonal variation in the immunoglobulin heavy chain gene suggests a process of clonal diversification rather than clonal selection in the early stages of disease progression. CLL-phenotype MBL is detectable in approximately 10% of cases referred for investigation of a lymphocytosis and future studies should be directed towards the detection of factors which identify MBL patients at risk of disease progression.     

Chronic lymphocytic leukemia‐associated immune thrombocytopenia treated with rituximab: a retrospective study of 21 patients

Introduction: There are no standard therapies for chronic lymphocytic leukemia (CLL)‐associated immune thrombocytopenia (IT) so far. Patients and methods: We report the results of therapy with single agent rituximab in 21 patients with CLL‐associated IT. The mean age at CLL and IT diagnosis was 64 and 68 yr, respectively. IT developed at a mean time of 44 months from the diagnosis of CLL. In four cases, IT was diagnosed at the same time as CLL. For three patients, IT was considered fludarabine‐related and two patients showed autoimmune hemolysis also. All patients but one received steroids as first‐line treatment for IT. Some patients received intravenous high‐dose Ig, vincristine, and Cytoxan also, without beneficial effect. After a mean time of 43 d from the diagnosis of IT, all patients were scheduled to receive rituximab at a dosage of 375 mg/mq/weekly. Results: Eighteen (86%) patients completed the scheduled four cycles of rituximab. Irrelevant first infusion side effects were seen only in one patient. Twelve (57%) patients showed a complete response (CR), six (29%) patients a partial response (PR), and three (14%) patients did not respond. In responding patients, the mean duration of response was 21 months (4–49 months). At a mean follow‐up of 28 months, 14 (66%) patients were still alive, 10 (48%) of them in CR and three (14%) in PR. Conclusions: This retrospective analysis prove that rituximab is an effective and well‐tolerated alternative treatment for CLL‐associated IT.     

Successful treatment of a patient with hairy cell leukemia and pentostatin-induced autoimmune thrombocytopenia with rituximab

The treatment of choice for hairy cell leukemia (HCL) are the purine analogs pentostatin and cladribine. They induced complete remissions in up to 85% of patients. Purine analogs are known to induce autoimmune phenomena, but there are no reports of autoimmune thrombocytopenia after treatment with pentostatin. This case report describes the very rare association of pentostatin-treated hairy cell leukemia and autoimmune thrombocytopenia. Encouraged by first reports of promising activity of the anti-CD20 monoclonal antibody rituximab in patients with autoimmune disorders, we decided to treat our patient with rituximab in the conventional dose of 375 mg/m(2) i.v. weekly for 4 cycles. One week after the first administration, the peripheral blood count has recovered with a normal platelet count. 22 weeks after completion of therapy, the patient is still in complete hematologic remission without further medication. In conclusion, rituximab seems to be a new, promising drug in the treatment of refractory autoimmune thrombocytopenia even in patients with underlying lymphoproliferative disorders.     

Autoimmune hyperthyroidism and thrombocytopenia developing in a patient with chronic lymphocytic leukemia

A 56-year-old white man is described whose course of chronic lymphocytic leukemia (CLL) was complicated by the occurrence of the autoimmune hyperthyroidism/thrombocytopenia syndrome. The implications of this syndrome on the treatment of CLL are discussed.     

Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia

A pilot study previously demonstrated that thrice-weekly, fractionated-dose intravenous rituximab (RTX) limits CD20 loss from chronic lymphocytic leukemia (CLL) B cells, thereby enhancing immunotherapeutic targeting. Here, we investigated the feasibility of giving 20 mg rituximab subcutaneously thrice weekly for up to 12 weeks in 4 previously treated CLL patients. Subcutaneous rituximab was well-tolerated with minimal injection site reactions; a variable degree of efficacy was observed, likely influenced by the size of the patients’ B cell/CD20 burden. Subcutaneous RTX largely preserved CD20 expression on leukemic cells but the most effective therapeutic dosing regimen needs to be established (ClinicalTrials.gov Identifier: NCT00366418).     

Multiple myeloma, chronic lymphocytic leukaemia and associated precursor diseases

Multiple myeloma and chronic lymphocytic leukaemia share common biological and clinical features including the presence of defined precursor conditions (monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis respectively). Here, we discuss evidence from the literature on the potential aetiological roles for genetic and chronic immune stimulatory factors on the pathway from precursor to malignancy. Also, we speculate on the relationship between precursor and malignancy and talk about future directions and gaps in the literature.     

Mechanism of autoimmune hemolytic anemia in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a malignant clonal expansion of CD5+B lymphocytes. The CD5+B lymphocytes have been postulated to produce autoantibodies. CLL patients may demonstrate features of autoimmunity including autoimmune hemolytic anemia. However, the origin of the autoantibodies causing the hemolysis is not clear. The present studies were performed to determine whether these autoantibodies are the products of the neoplastic B-CLL clones. Immunoglobulins (Ig) were eluted from washed red blood cells (RBC) obtained from two CLL patients at the time they had autoimmune (DAT-direct antiglobulin test - positive) hemolytic anemia. The light chain phenotypes of these eluted autoantibodies were determined and found to be monotypic with exact correlation to the light chain expressed on the surface of the B-CLL clones. Elutions from RBC of DAT negative patients or normal volunteers failed to demonstrate measurable amounts of Ig. In contrast, Ig eluted from RBC obtained from SLE patients with DAT positive hemolytic anemia found to be polyclonal autoantibodies exhibiting both light chain types. Furthermore, CD5+B lymphocytes obtained from the same two CLL patients (DAT+) produce, in vitro understimulation with phorbal myristate acetate (PMA), monoclonal antibodies which react and bind to RBC. Thus these studies provide direct evidence demonstrating that the antibodies causing the autoimmune hemolytic anemia in our two CLL patients are the products of the B-CLL neoplastic clones.     

Genetic modification of primary chronic lymphocytic leukemia cells with a lentivirus expressing CD38

Studies of the role of individual genes in chronic lymphocytic leukemia (CLL) have been hampered by the inability to consistently transfect primary tumor cells. Here, we describe a highly efficient method of genetically modifying primary CLL cells using a VSVG pseudotyped lentiviral vector. We transduced CD38 negative CLL cells with a lentiviral vector encoding CD38 which caused increased surface CD38 expression in all the samples tested (n=17) with no evidence of plasmacytoid differentiation. The mean percentage of positive cells expressing CD38 was 87%±8.5% and the mean cell viability 74%±17%. This high level of transduction of all the CLL cell samples tested demonstrates the utility of this technique which should prove applicable for the introduction and analysis of other genes in these non-dividing cells.     

B cells CD19+ in patients with B‐cell chronic lymphocytic leukaemia and autoimmune haemolytic anaemia

The study presents results of B and T lymphocytes population analysis in patients with chronic lymphocytic leukaemia B cells and autoimmune haemolytic anaemia (CLL‐B + AIHA). We evaluated the following groups of patients: (1) with newly recognized CLL‐B and co‐existent AIHA (untreated), (2) after short‐term treatment with corticosteroids, (3) after treatment with chemotherapy and corticosteroids. The control groups were made of patients with CLL‐B without AIHA. The populations of lymphocytes and determination of cells immunophenotype were performed by means of flow cytometry. The analysed data were obtained from 25 patients. The untreated patients with CLL‐B + AIHA presented significantly more numerous population of neoplastic cells CD19+ CD5+ in comparison with patients without AIHA. The patients with AIHA showed a reduced percentage of B CD19+ CD22+ cells in comparison with those without AIHA. Untreated patients with AIHA or after a short‐term corticosteroid treatment showed a higher ratio of the number of CD19+ CD5+ cells to the number of T CD4+ and T CD8+ lymphocytes than CLL‐B patients without AIHA. It can be presumed that the differences found may be related to the pathogenesis of the autoimmune haemolysis syndrome in patients with CLL‐B.     

慢性淋巴细胞白血病检测t(11;14)、CD5和CD23的诊断价值

目的:探讨慢性淋巴细胞白血病(CLL)检测t(11;14)、CD5和CD23的诊断价值.方法:采用流式细胞术(FCM)和常规细胞遗传学(CC)对45例初诊为CLL的患者进行免疫学和细胞遗传学检测,并采用间期荧光原位杂交(FISH)技术进行t(11;14)的研究.结果:45例初诊CLL中,CC均未见t(11;14)异常,...     

Successful percutaneous coronary intervention using bivalirudin in a patient with chronic lymphocytic leukemia and thrombocytopenia

A patient with chronic lymphocytic leukemia and thrombocytopenia who underwent percutaneous coronary intervention (PCI) and stenting is presented. Patients with these concomitant diseases who require invasive cardiac procedures are at increased risk for ischemic and bleeding complications and the choice of anticoagulation in these patients is critical. In the present case, anticoagulation was achieved with the direct thrombin inhibitor bivalirudin. No complications were reported, and the patient tolerated the procedure well. This case suggests that bivalirudin may be safely used in patients who are at an increased risk of bleeding undergoing PCI.     

In vitro production of anti-RBC antibodies and cytokines in chronic lymphocytic leukemia

B-chronic lymphocytic leukemia (B-CLL) patients have a high prevalence of autoimmune phenomena, mainly autoimmune hemolytic anemia (AIHA). Immunoregulatory cytokines play a role in the regulation of both autoimmunity and leukemic B-cell growth. Mitogen-stimulated direct antiglobulin test (MS-DAT) is a recently described test able to disclose latent anti-RBC autoimmunity in AIHA. We investigated the prevalence of anti-RBC autoimmunity by MS-DAT and the pattern of cytokine production by PHA-stimulated whole blood cultures from 69 B-CLL patients and 53 controls. Results showed that anti-RBC IgG values in unstimulated, PHA-, PMA-, and PWM-stimulated cultures were significantly higher in B-CLL patients compared with controls. In B-CLL, the prevalence of anti-RBC autoimmunity was 28.9% by MS-DAT, compared with 4.3% by the standard DAT. Production of IFN-gamma, IL-2, IL-13, TNF-alpha, sCD23, and sCD30 was significantly increased in all B-CLL patients compared with controls, whereas there was no difference in IL-4, IL-6, IL-10, and TGF-beta production. Multivariate analysis showed that IL-4 was significantly increased in MS-DAT-positive compared with -negative patients. Patients with autoantibody positivity displayed greater IFN-gamma production than negative patients. These data are in line with the hypothesis that autoimmune phenomena in B-CLL are associated with an imbalance towards a Th-2-like profile. The elevated prevalence of anti-RBC autoimmunity found by MS-DAT suggests that an underestimated latent autoimmunity exists in B-CLL.     

Prognostic value of CD20 antigen mediated immune checkpoint inhibition in patients with acute or chronic lymphocytic leukemia: A protocol for systematic review

Background:The addition of rituximab to standard chemotherapy has been shown to improve response rates in patients with acute or chronic lymphocytic leukemia. However, the prognostic factors associated with progression-free survival in rituximab treated patients with lymphocytic leukemias remains unclear. We will perform a comprehensive systematic review and meta-analysis on available data on prognostic factors associated with the clinical outcomes of patients with acute and chronic lymphocytic leukemia.Methods and analysis:This protocol for a systematic review and meta-analysis of prognostic factors has been prepared following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 guidelines. Electronic databases will be searched using keywords related to the objectives of this review. This systematic review and meta-analysis will include published randomized clinical trials, observational, prospective, and retrospective comparative cohorts. Two reviewers (ZAM and SAM) will independently screen studies, with a third reviewer consulted in cases of disagreements using a defined inclusion and exclusion criteria. Data items will be extracted using a predefined data extraction sheet. Moreover, the risk of bias and the quality of evidence were independently assessed using the quality in prognostic studies tool (QUIPS). The I2 and chi squared statistical tests will be used to analyze statistical heterogeneity across studies. An I2 values of > 50% will be considered substantial. All data analysis will be performed using STATA 16.0 (StataCorp LP, TX, USA). The outcomes examined will be progression-free and overall survival.Ethics and dissemination:No ethical approval will be required and the findings of this meta-analysis will be published in a peer-reviewed journal.Systematic review registration:International prospective Register of Systematic Reviews (PROSERO) number: CRD42021218997.     

Circulating CD52 and CD20 levels at end of treatment predict for progression and survival in patients with chronic lymphocytic leukaemia treated with fludarabine,cyclophosphamide and rituximab (FCR)

CD52 and CD20 antigens are important therapeutic targets for the monoclonal antibodies (mAbs) alemtuzumab and rituximab respectively. Circulating CD52 (cCD52) and CD20 (cCD20) have prognostic utility in lymphoid malignancies. The efficacy of mAb therapy in patients with chronic lymphocytic leukaemia (CLL) may be adversely affected by cCD52 or cCD20. In this report, blood and bone marrow (BM) cCD52 and cCD20 were measured at response assessment in previously treated (N = 235) patients with CLL who received fludarabine, cyclophosphamide, and rituximab (FCR). Univariate and multivariate statistical models evaluated correlations of pre‐ and response variables with progression‐free (PFS) and overall survival (OS). Response variables included 1996 National Cancer Institute‐Working Group (NCI‐WG) response, polymerase chain reaction (PCR) for immunoglobulin heavy chain (IGHV) in BM, and cCD52 and cCD20 levels (blood and BM) at response assessment. Using multivariate analysis, response blood and BM cCD52, blood cCD20, and NCI‐WG response were significant independent predictors of PFS. At the time of response assessment, BM cCD52 correlated with OS in univariate analysis. cCD52 and cCD20, therefore appear useful in predicting survival and may be important for monitoring patients following salvage FCR (fludarabine, cyclophosphamide, rituximab) therapy. These data further indicate that plasma may be a good target to evaluate for minimal residual disease using cCD52/cCD20 levels.